The present invention relates to compositions and methods for prevention or reduction of symptoms associated with mastalgia and endometriosis by administering phytochemicals. Among the phytochemicals useful in the compositions and methods of the invention are dietary indole, Diindolylmethane (DIM), as well as its precursor, Indole-3-carbinol (I3C), and cogener, 2-(Indol-3-ylmethyl)-3,3xe2x80x2-diindolylmethane (LTR-1).
In the typical life-cyle of modern women, the mid-thirties until the cessation of menstrual periods is defined as xe2x80x9cperi-menopausexe2x80x9d. Women are classified as perimenopausal if menses have been experienced in the last 12 months, but with irregularity or changes in menstrual flow. During this stage of life women suffer increasing incidence of both recurrent breast pain, or xe2x80x9cmastalgiaxe2x80x9d, and endometriosis, describing the painful condition of persistence of abnormal endometrial tissue in the abdominal cavity. These two conditions, common to the perimenopause, are poorly understood and presently lack medical therapy that is both effective and reasonably free of side effects. (Prior, J. C., xe2x80x9cPerimenopause: the complex endocrinology of the menopausal transitionxe2x80x9d, Endocr. Rev. , 19, pages 397-428, 1998).
While a contributing role of estrogen status has been suspected in these conditions, few consistent abnormalities in endocrine status have been identified. Circulating estrogen levels are normal in both mastalgia and endometriosis patients. There is accumulating evidence that describes diminished progesterone production during the perimenopause that may create a relative xe2x80x9cdominancexe2x80x9d in the activity of estrogen. However, no one theory or endocrine imbalance explains the occurrence of mastalgia and endometriosis. (Santoro, N., Rosenberg, J., et al.,xe2x80x9cCharacteristics of reproductive hormonal dynamics in the perimenopausexe2x80x9d, J. Clinical Endocrinology and Metab., 81, pages 1495-501, 1996).
Recurrent, cyclical breast pain or xe2x80x9cmastalgiaxe2x80x9d is one of the most common reasons for women""s visits to their doctors. It has been estimated that 50-70% of all women experience significant mastalgia at some point in their life. In its most common form, mastalgia is a chronic condition of recurring pain, which is worse during the few days before menses (Blue, J., Harman, J., et al., xe2x80x9cMastalgia review: St. Marks Breast Centrexe2x80x9d, New Zealand Medical Journal, 111(1059), pages 33-34, 1998). Traditionally, treatment choices for mastalgia have ranged from dietary manipulation (caffeine, fat, and alcohol reduction) or evening primrose oil to hormonal medications (bromocriptine and danazol) for severe breast pain. Bromocriptine (Parlodel) and danazol have a response rate of 70%, but have reported adverse side effects of up to 30-35% (Gateley, C. A. and Mansen, R. E., xe2x80x9cManagement of the painful and nodular breastxe2x80x9d, British Medical Bulletin, 47, 284-94, 1991; Nazli K., et al. Controlled trial of the prolactin inhibitor bromocriptine (Parlodel) in the treatment of severe cyclical mastalgia. British Journal of Clinical Practice. 1989; 43(9): 322-7; Kontosolis K. et al., Comparison of tamoxifen with danazol for treatment of cyclical mastalgia. Gynecol. Endolcrinol. 1997; 11, page 393-397). The use of medroxyprogesterone acetate to support levels of progesterone, possibly low in this condition, proved relief no better than placebo in a controlled trial. (Maddox, P. R., Harrison, B. J., et al., xe2x80x9cA randomized controlled trial of medroxyprogesterone acetate in mastalgiaxe2x80x9d, Annals of the Royal College of surgeons of England, 72(2), pages 71-6, 1990).
The approach of dietary supplementation for mastalgia has been explored by earlier investigators. This included the addition of high doses of evening primrose oil, beta carotene, and vitamin A to the diet of affected women. Evening primrose oil is used by British physicians as an initial intervention to control mastalgia because of its non-hormonal composition. Though it has been found to normalize the ratio of essential fatty acids to saturated fatty acids in the serum of women with mastalgia, the therapy requires 3 to 4 months for benefit. Improvements were seen in up to 40% of patients but side effects included bloating and nausea (Maddox, P. R., xe2x80x9cThe management of mastalgia in the UKxe2x80x9d, Hormone Research, 32, pages 21-27, 1989). Italian researchers explored the addition of combinations of beta carotene and Vitamin A (retinol) in the management of mastalgia. (Santamaria L, Dell""Orti, M., et al., xe2x80x9cBeta-carotene supplementation associated with intermittent retinol administration in the treatment of pre-menopausal mastodynia,xe2x80x9d, Boll Chim Far, 128, pages 284-287, 1989). Some success was reported, but the high doses of retinol required (150-300,000 I.U per day) are in the range associated with significant side effects which include headache, skin lip and mouth dryness, nausea, dizziness, and alopecia. Based on the common occurrence of mastalgia as a disorder in women, the need exists for more effective therapy with acceptable risks and side effects (Ashley B., xe2x80x9cMastalgiaxe2x80x9d, Lippincotts Primary Care Practice. 1998; 2(2): 189-93).
Endometriosis is a disease that affects as many as 15% of fertile women and up to 50% of infertile women. Its occurrence increases with age and is greatest in the perimenopausal years (Tzingounis V A, and Cardamakis E., xe2x80x9cModern approach to endometriosisxe2x80x9d, Annals of the New York Academy of Sciences, 816, pages 320-330, 1997). Endometriosis refers to the presence of functional endometrial glands and stroma in abnormal locations outside the uterine cavity. Despite extensive research, the natural history and pathogenisis of endometriosis is still poorly understood and remains controversial. As with mastalgia, most therapeutic approaches have been directed at hormonal therapy. The most common therapy involves the use of danazol. Danazol is a synthetic steroid with androgenic action suppressing the pituitary gland cycling necessary for menstrual periods. Amenorrhea, or lack of menstrual periods results. Though providing some relief from the pain of endometriosis adverse side effects are experienced in up to 80% of women using Danazol (Greenblatt R B, Dmowski, W. P., et al. xe2x80x9cClinical studies with an anti-gonadotropinxe2x80x94danazolxe2x80x9d, Fertil Steril, 22, page 102, 1971). Notably these side effects include weight gain, fluid retention, acne, decreased breast size, hot flushes and mood changes. In addition to danazol, other hormonal manipulations used in the management of endometriosis involve use of gonadotropin releasing hormone analogues (GnRH) and the drug gestrinone, a synthetic steroid derived from 19-nortestosterone. The side effects associated with these therapies are significant and include the spectrum of symptoms associated with hypoestrogenism and menopause. These include hot flushes, night sweats, and osteoporosis. (Telimaa, E. J., Puolakka, J., et al., xe2x80x9cPlacebo-controlled comparison of danazol and high-dose medroxyprogesterone acetate in the treatment of endometriosisxe2x80x9d, Gynecol Endocrinol, 1, page 51, 1987, and Thomas E. J., Cooke, I. D., et al., xe2x80x9cImpact of gestrinone on the course of asymptomatic endometriosisxe2x80x9d, Br. Med J., 294, page 272, 1987). Clearly, more benign approaches to the management of the pain of endometriosis are needed.
Diindolylmethane (DIM), as well as its precursor, Indole-3-carbinol (I3C), and cogener, 2-(Indol-3-ylmethyl)-3,3xe2x80x2-diindolylmethane (LTR-1) are natural phytochemicals and part of the family of dietary indoles discovered in cruciferous vegetables. DIM and I3C are found in cruciferous vegetables including broccoli, cauliflower, cabbage and Brussels sprouts (Bradfield C A and Bjeldanes L F, High performance liquid chromatographic analysis of anticarcinogenic indoles in Brassica oleracea. J Agric. Food Chem. 1987; 35:46-49). DIM, together with the linear trimer, LTR-1, are formed from the precursor indole, I3C, after the enzymatic release of I3C from parent glucosinolates found in all cruciferous vegetables.
It is now known that there is a connection between dietary cruciferous indoles and estrogen metabolism. H. Leon Bradlow, Ph.D. and his group at the Strang Cancer Prevention Laboratory in New York were the first to establish the link between phytonutrients from cruciferous vegetables and estrogen metabolism. They showed that supplemental use of a I3C can act to promote a dramatic change in the metabolism of estrogen Michnovicz J J, et al., Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans. J Natl Cancer Inst. May 21, 1997; 89(10):718-23. This change in metabolism has the power to greatly reduce estrogen exposure as a risk for cancer and provides a dietary approach to improving estrogen metabolism. When cruciferous phytochemicals are added to the diet its metabolism is shifted. This produces a predominance of 2-hydroxy and 2-methoxyestrogens (Michnovicz J J, et al., Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans. J Natl Cancer Inst. May 21, 1997; 89(10):718-23). An increased proportion of 2-hydroxy metabolites is correlated to protection from breast cancer. This relationship has been documented in case-control studies (Ho G H, et al. Urinary 2/16 alpha-hydroxyestrone ratio: correlation with serum insulin-like growth factor binding protein-3 and a potential biomarker of breast cancer risk. Ann Acad Med Singapore 1998; 27:294-299, and Schneider J., et al., Abnormal oxidative metabolism of estradiol in women with breast cancer. Proc Natl Acad Sci USA 1982; 79: 3047-3051). The 2-hydroxy metabolites have been called xe2x80x9cgood estrogens (Bradlow H L, et al., 2-hydroxyestrone: the xe2x80x98goodxe2x80x99 estrogen. J Endocrinol. 1996 Sep; 150 Suppl:S259-65), and may function as antioxidants (Komura S, et al., Catecholestrogen as a natural antioxidant. Ann N Y Acad Sci. Jun. 15, 1996; 786:419-429).
With regard to prior art and the dietary indoles, the supplemental use of I3C, which converts to DIM and LTR-1 after passage through the stomach, has been the subject of a U.S. Pat. No. 5,895,787 describing the use of I3C and related dietary indoles to reduce the symptoms of fibromyalgia. Despite this use, no relationship between fibromyalgia and estrogen status has been documented (Bengtsson A., Henriksson, K. G., xe2x80x9cPrimary fibromyalgia. A clinical and laboratory study of 55 patients.xe2x80x9d, Scand J. Rheumatol, 15(3), pages 340-7, 1986) Published reports have demonstrated the usefulness of dietary supplementation with I3C in recurrent laryngeal papillomatosis and cervical dysplasia. (Rosen, C. A., Woodson, G. E. et al., xe2x80x9cPreliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis, Otolaryngology Head Neck Surgery, 118, pages 810-5, 1998, and Jin L., Qi, M., et al., xe2x80x9cIndole-3-carbinol prevents cervical cancer in human papilloma virus type 16 (HPV16) transgenic micexe2x80x9d, Cancer Research, 59(16), pages 3991-7, 1999) These are both diseases related to the action of the human papilloma virus and may represent conditions sensitive to estrogen metabolic status. Use of DIM and LTR-1 in absorption enhancing formulations for improving the balance of estrogen metabolites has been the subject of earlier investigation by the present inventor and provides the basis of U.S. Pat. No. 6,086,915. This prior work has allowed for the present investigation of the use dietary indoles as dietary supplements to beneficially impact mastalgia and endometriosis.
While previous work with dietary indoles, like DIM, has indicated their ability to impede the growth of breast cancer in animals (Chen, I., McDougal, A., et al., xe2x80x9cAryl hydrocarbon receptor-mediated antiestrogenic and antitumorigenic activity of diindolylmethane,xe2x80x9d Carcinogenesis, 19(9), 1631-9, 1998) no reports exist as to the usefulness of cruciferous phytochemicals in managing mastalgia or endometriosis.
The present invention relates to compositions and methods for prevention or reduction of symptoms associated with mastalgia and endometriosis by administering phytochemicals, e.g., dietary indoles. In a preferred embodiment, the pain associated with endometriosis and mastalgia is prevented or reduced. In another embodiment, the presence of a marker associated with endometriosis is reduced through phytochemical treatment. Among the phytochemicals useful in the compositions and methods of the invention are dietary indole, Diindolylmethane (DIM), as well as its precursor, Indole-3-carbinol (I3C), and cogener, 2-(Indol-3-ylmethyl)-3,3xe2x80x2-diindolylmethane (LTR-1).
Also according to the present invention, a pharmaceutical composition is provided, which comprises a phytochemical, preferably I3C, DIM and/or LTR-1, and, optionally, pharmaceutically acceptable carriers.
The present invention is based upon the observation that administration of phytochemicals, in particular, I3C, DIM, and LT-1, has improved symptoms of mastalgia and endometriosis.
The facilitated delivery of DIM and related indoles as dietary supplements may be accomplished according to formulations and methods described in U.S. Pat. No. 6,086,915. The effectiveness of supplemental DIM is further supported by co-administration of phytochemicals (e.g., DIM, LTR-1) with grapefruit concentrate, which additionally facilitates the absorption of phytochemicals (e.g., DIM, LTR-1).
The invention provides compositions and methods for prevention or reduction of symptoms associated with mastalgia. In a preferred embodiment, breast pain of subjects suffering from mastalgia is prevented, reduced and/or eliminated through the administration of phytochemicals, e.g., dietary indoles, in a pharmaceutically acceptable fashion. In preferred embodiments, the phytochemicals are DIM, I3C and LTR-1. In particular embodiments, I3C, DIM, or LTR-1, alone or in combination with each other or other dietary supplements, are administered orally in, for example, the form of encapsulated dietary supplements.
The I3C is preferably administered at a dose of 200-500 mg per day. In alternative embodiments, I3C is administered at doses of 200-300 mg per day, 300-400 mg per day and 400-500 mg per day.
DIM is administered providing 150-500 mg per day of DIM. In preferred embodiments, the dose of DIM, I3C or LTR-1 is 150-200 mg per day, 200-300 mg per day, 300-400 mg per day, and 400-500 mg per day.
In a preferred embodiment, DIM is administered in an absorption enhancing formulation, as described in U.S. Pat. No. 6,086,915, providing 60-500 mg per day of DIM suspended as microparticles in a starch carrier matrix. In preferred embodiments, the dose of processed DIM is 60-100 mg per day, 100-200 mg per day, 200-300 mg per day, 300-400 mg per day, and 400-500 mg per day.
The LTR-1 is preferably administered in an absorption enhancing formulation providing 60-500 mg per day of LTR-1 suspended as microparticles in a starch carrier matrix as previously described, however, the present invention contemplates the administration of any preparation of LTR-1. In a preferred embodiment, the dose of LTR-1 is 150-200 mg per day. In preferred embodiments, the dose of processed LTR-1 is 60-100 mg per day, 200-300 mg per day, 300-400 mg per day, and 400-500 mg per day.
Doses of the phytochemicals of the invention can also be calculated based upon the body weight of the subject to be treated. Doses of phytochemicals between 0.5 and 3 mg per kg of body weight per day are preferred. In another preferred embodiment, the phytochemicals are administered at a dose of between 0.5 and 2.0 mg per kg per day, preferably 1.5 mg per kg per day.
Alternatively, the co-administration of grapefruit, grapefruit concentrate, grapefruit juice, or grapefruit juice concentrate, or other grapefruit-derived composition along with a dietary indole (e.g., I3C, DIM or LTR-1) can be used to increase absorption of the phytochemicals and promote even more efficient relief from the symptoms of mastalgia.
In an alternative embodiment, the dietary indole (e.g., DIM or LTR-1) is administered in the form of a liposomal sublingual spray applied directly to the oral mucosa. This liposomal suspension provides phytochemical loaded liposomes to administer the phytochemicals and create a sustained delivery system. Dietary indole (e.g., DIM or LTR-1) containing liposomes are sequestered in the oral mucosa, allowing absorption which avoids xe2x80x9cfirst passxe2x80x9d hepatic metabolism. The liposomal spray uses standard liposomal preparation and structural lipid ingredients (Ranade, V. V., xe2x80x9cDrug delivery systems. 1. Site-specific drug delivery using liposomes as carriers,xe2x80x9d J. Clin. Pharmacol. 29(8):685-94, 1989). In a preferred embodiment, the liposomal spray is administered at a dose of 5-30 mg of dietary indole (e.g., DIM or LTR-1) daily delivered in 2-12 sprays of a typical liposomal preparation.
Alternatively the phytochemicals (e.g., DIM or LTR-1) may be administered in the form of a transdermal cream applied directly to the skin. This cream utilizes various absorption enhancing emollients and consists of phytochemical (e.g., DIM or LTR-1) in a concentration of 1-3% by weight. It is designed as a moisturizing cosmetic that is formulated to allow application directly to painful breasts in women not wishing to take phytochemicals orally. Formulations are also made with the neurohormone, melatonin, to provide a nighttime cosmetic mosturizer offering the benefits of melatonin in combination with the phytochemical (e.g., DIM or LTR-1). This allows application of cruciferous indoles and melatonin directly to underlying breast tissue with the added benefit of sleep regulating action from melatonin. In a particular embodiment, application of from 5-10 cc of the transdermal preparation daily is used to administer from 5-30 mg of DIM or other dietary indole per day, and optionally, 3-10 mg of melatonin per day.
Alternatively, the phytochemical (e.g., DIM or LTR-1) may be administered in the form of a vaginal cream or suppository containing microcrystalline phytochemical (e.g., DIM or LTR-1) in a combined dose of 20-100 mg. This allows application of cruciferous indoles directly to vaginal and cervical mucosa for the benefit of cervical dysplasia.
The phytochemicals of the invention may be administered in any appropriate amount in any suitable galenic formulation and following any regime of administration.
The actual administered amount of phytochemical may be decided by a supervising physician and may depend on multiple factors, such as, the age, condition, file history, etc., of the patient in question.
The subject, or patient, to be treated using the methods of the invention is an animal, e.g., a mammal, and is preferably human, and can be a fetus, child, or adult. In a preferred embodiment, the subject is a human female.
The invention provides compositions and methods for reduction or prevention of symptoms associated with endometriosis. In a preferred embodiment, the pain of subjects suffering from endometriosis is prevented, reduced and/or eliminated through the administration of phytochemicals in a pharmaceutically acceptable fashion. In another preferred embodiment, the levels of an endometriosis marker (e.g., Ca-125 antigen, a serum marker of endometriosis) in subjects suffering from endometriosis is lowered through the administration of phytochemicals in a pharmaceutically acceptable fashion. In preferred embodiments, the phytochemicals are DIM, I3C and LTR-1. In particular embodiments, I3C, DIM, or LTR-1, alone or in combination with each other or other dietary supplements, are administered orally in, for example, the form of encapsulated dietary supplements.
The I3C is preferably administered at a dose of 200-500 mg per day. In alternative embodiments, I3C is administered at doses of 200-300 mg per day, 300-400 mg per day and 400-500 mg per day.
DIM is administered providing 30-500 mg per day of DIM. In preferred embodiments, the dose of DIM, I3C or LTR-1 is 30-100 mg per day, 100-200 mg per day, 200-300 mg per day, 300-400 mg per day, and 400-500 mg per day.
In a preferred embodiment, DIM is administered in an absorption enhancing formulation, as described in U.S. Pat. No. 6,086,915, providing 30-500 mg per day of DIM suspended as microparticles in a starch carrier matrix. In preferred embodiments, the dose of processed DIM is 30-100 mg per day, 100-200 mg per day, 200-300 mg per day, 300-400 mg per day, and 400-500 mg per day.
The LTR-1 is preferably administered in an absorption enhancing formulation providing 30-400 mg per day of LTR-1 suspended as microparticles in a starch carrier matrix as previously described, however, the present invention contemplates the administration of any preparation of LTR-1. In a preferred embodiment, the dose of LTR-1 is 100-200 mg per day. In preferred embodiments, the dose of processed LTR-1 is 30-100 mg per day, 200-300 mg per day, 300-400 mg per day, and 400-500 mg per day.
Doses of the phytochemicals of the invention can also be calculated based upon the body weight of the subject to be treated. Doses of phytochemicals between 1 and 3 mg per kg of body weight per day are preferred. In another preferred embodiment, the phytochemicals are administered at a dose of between 1.5 and 2.5 mg per kg per day, preferably 2.0 mg per kg per day.
Alternatively, the co-administration of grapefruit, grapefruit concentrate, grapefruit juice, or grapefruit juice concentrate, or other grapefruit-derived composition along with I3C, DIM or LTR-1 can be used to increase absorption of the phytochemicals and promote even more efficient relief from the symptoms of endometriosis, including the reduction of markers associated with endometriosis.
In an alternative embodiment, the phytochemical (e.g., DIM or LTR-1) is administered in the form of a liposomal sublingual spray applied directly to the oral mucosa. This liposomal suspension provides phytochemical loaded liposomes to administer the phytochemicals and create a sustained delivery system. DIM and LTR-1 containing liposomes are sequestered in the oral mucosa, allowing absorption which avoids xe2x80x9cfirst passxe2x80x9d hepatic metabolism. The liposomal spray uses standard liposomal preparation and structural lipid ingredients. (Ranade, V. V., xe2x80x9cDrug delivery systems. 1. Site-specific drug delivery using liposomes as carriers,xe2x80x9d J. Clin. Pharmacol. 29(8):685-94, 1989; Crommelin, D. J. A. and Schreir, H., xe2x80x9cLiposomesxe2x80x9d, Colloidal Drug Delivery Systems, Kreuter, J. editor, Marcel Dekker, N.Y., 1994, p. 85). In a preferred embodiment, the liposomal spray is administered at a dose of 5-30 mg of phytochemical daily delivered in 2-12 sprays of a typical liposomal preparation.
Alternatively the phytochemicals (e.g., DIM or LTR-1) may be administered in the form of a transdermal cream applied directly to the skin. This cream utilizes various absorption-enhancing emollients and consists of DIM or LTR-1 in a concentration of 1-3% by weight. It is designed as a moisturizing cosmetic which is formulated to allow application directly to the skin of women not wishing to take phytochemicals orally. Formulations are also made with the neurohormone, melatonin, to provide a nighttime cosmetic moisturizer offering the benefits of melatonin in combination with the phytochemical (e.g., DIM or LTR-1). This provides the added benefit of sleep regulating action from melatonin. In a particular embodiment, application of from 5-10 cc of the transdermal preparation daily is used to administer from 5-30 mg of phytochemical (e.g., DIM or LTR-1) per day, and optionally, 3-10 mg of melatonin per day.
Alternatively the phytochemical (e.g., DIM or LTR-1) may be administered in the form of a vaginal cream or suppository containing microcrystalline DIM or LTR-1 in a combined dose of 20-100 mg. This allows application of cruciferous indoles directly to vaginal and cervical mucosa for the benefit of cervical dysplasia.
The phytochemicals of the invention may be administered in any appropriate amount in any suitable galenic formulation and following any regime of administration.
The actual administered amount of phytochemical may be decided by a supervising physician and may depend on multiple factors, such as, the age, condition, file history, etc., of the patient in question.
The subject, or patient, to be treated using the methods of the invention is an animal, e.g., a mammal, and is preferably human, and can be a fetus, child, or adult. In a preferred embodiment, the subject is a human female.
The pharmaceutical compositions according to the present invention preferably comprise one or more pharmaceutically acceptable carriers and the active constituents. The carrier(s) must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
It will be appreciated that the amounts of phytochemical required for said treatment will vary according to the route of administration, the disorder to be treated, the condition, age, and file history of the subject, the galenic formulation of the pharmaceutical composition, etc.
Preferably, the phytochemical used in the invention has been processed to enhance bioavailability, as is described in U.S. patent application Ser. No. 09/053,180. So processed DIM or LTR-1 is referred to as xe2x80x9cprocessed DIMxe2x80x9d and xe2x80x9cprocessed LTR-1xe2x80x9d, respectively. However, any suitable preparation of phytochemical can be used in the methods and compositions of the invention.
The following is a list of ingredients useful for formulating processed DIM or LTR-1:
1. About 10 to about 40 percent by weight of LTR-1 or DIM.
2. About 10 to about 40 percent by weight of the following, alone or in combination: vitamin E succinate polyethylene glycol 1000; vitamin E succinate Polyethylene glycols with polyethylene glycol (with a molecular weight range of 400-2000); other polyethylene glycol esters such as those formed by fatty acids such as oleic acid or stearic acid; polyvinylpyrrolidones; polyvinylpolypyrrolidones; Poloxamer 188, Tweens; or Spans.
3. About 5 to about 20 percent by weight of the following, alone or in combination: phosphatidyl choline (derived from soy lecithin and supplied as Phospholipon 50G from Rhone Poulenc Rorer); dioleoyl phosphatidylcholine; phoshatidylglycerol; dioleoylphosphatidylglycerol; dimyristoylphosphatidylcholine; dipalmitoylphosphatidylcholine; phosphatidylethalolamines; phosphatidylserines; or sphingomyelins; or other sources of phospholipids as those from purified Milk Fat Globule Membrane; glycerolesters; poly glycerol esters; or ethoxylated castor oil.
4. About 15 to about 30 percent by weight of the following, alone or in combination: hexanol; ethanol; butanol; heptanol; 2-methyl-1-pentanol; various ketone solvents that would be acceptable in foods such as methyl ethyl ketone, acetone and others; propylene glycol; and certain ester solvents such as ethyl acetate.
5. About 20 to about 40 percent by weight of the following, alone or in combination: modified starch such as Capsul(trademark) Starch from National Starch, Inc.; methylcellulose; hydroxypropyl methylcellulose; hydroxyethylcellulose; hydroxypropylethylcellulose; pectin; gum arabic; gelatin; or other polymeric matrix-forming preparation known to those skilled in the art, soluble in water and, suitable for spray drying.
6. About 0.5 to about 35 percent by weight of the following, alone or in combination: aerosil 200; or any other flow enhancing excipient from silica, or related salt, known to those skilled in the art.
The following is a detailed method of formulating processed DIM:
1. 6.75 kg of TPGS is heated just beyond its melting point with constant stirring in a heated vessel (xe2x80x9cFirst vesselxe2x80x9d).
2. 9.38 kg of hexanol and 9.83 kg of jet milled DIM is added to the first vessel and the mixture stirred to a uniform suspension at 70xc2x0 C. 1.4 kg of phosphatidyl choline is then added.
3. In a second larger vessel, 185 L of water and 10.7 kg of starch are thoroughly mixed with a Cowles blade. This mixture is neutralized to pH 7 with a small amount of sodium carbonate and then heated to 75xc2x0 C. and stirred for 1 hour.
4. The contents of the first vessel is added to the starch mixture in the second larger vessel and thoroughly mixed with a homogenizing rotor/stator type mixer at moderate speed for 15 minutes.
5. The mixture from step 4 is spray dried with a small amount (approximately 0.5%) of hydrophilic silica to provide a free flowing powder of finely dispersed microparticles containing the co-precipitated TPGS, phosphatidyl choline and DIM in an amorphous, non-crystalline structure.
6. The flowable powder product is collected and stored in evacuated foil sacks, after de-aerating and flushing with nitrogen.
7. Analysis of presence of unchanged dietary ingredient, reveals about 30 to about 33 percent by weight of DIM.
The procedure of making processed DIM may be summarized as follows:
(a) heating one or more solubilizing emulsifiers selected from the group consisting of vitamin E succinate polyethylene glycol 1000, polyvinylpyrrolidone, polyoxyethylene stearate, sodium cholate, deoxycholate and taurocholate;
(b) adding to the product of step (a) a solvent and a surfactant phospholipid selected from the group consisting of phosphatidyl choline, dioleoyl phosphatidyl choline, phosphatidylglycerol, dioleoylphosphatidylglycerol, dimyristoylphosphatidylcholine, dipalitoylphosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and sphingomyelin to produce a solution;
(c) dissolving in the solution of step (b) LTR-1 and/or DIM;
(d) adding to the solution of step (c) a solution containing an encapsulator;
(e) mixing the solution produced in step (d) to produce a microdispersion with a particle size of 5 microns or less; and
(f) spray drying the resulting mixture to leave a solid hydrophobic phytochemical composition.
In general, a suitable (therapeutically effective) amount of I3C is 300-500 mg per day. DIM is preferably administered in an absorption enhancing formulation, as described in U.S. Pat. No. 6,086,915, at 50-200 mg per day as a suspension of microparticles in a starch carrier matrix. The LTR-1 is preferably administered in an absorption enhancing formulation at 50-200 mg per day as a suspension of microparticles in a starch carrier matrix. The actually administered amounts of phytochemical may be decided by a supervising physician. The phytochemicals of the invention may be administered alone or in combination with one another, and/or with other dietary supplements. The combinations of phytochemicals and supplements can be in the same composition for administering in combination concurrently, or in different compositions for administering concurrently but separately, or sequentially.
Therapeutic formulations include those suitable for parenteral (including intramuscular and intravenous), oral, rectal or intradermal administration, although oral administration is the preferred route. Thus, the pharmaceutical composition may be formulated as tablets, pills, syrups, capsules, suppositories, formulations for transdermal application, powders, especially lyophilized powders for reconstitution with a carrier for intravenous administration, etc.
The term xe2x80x9ccarrierxe2x80x9d refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. The carriers in the pharmaceutical composition may comprise a binder, such as microcrystalline cellulose, polyvinylpyrrolidone (polyvidone or povidone), gum tragacanth, gelatin, starch, lactose or lactose monohydrate; a disintegrating agent, such as alginic acid, maize starch and the like; a lubricant or surfactant, such as magnesium stearate, or sodium lauryl sulphate; a glidant, such as colloidal silicon dioxide; a sweetening agent, such as sucrose or saccharin; and/or a flavoring agent, such as peppermint, methyl salicylate, or orange flavoring.
Therapeutic formulations suitable for oral administration, e.g., tablets and pills, may be obtained by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by mixing phytochemicals, and compressing this mixture in a suitable apparatus into tablets having a suitable size. Prior to the mixing, the phytochemical may be mixed with a binder, a lubricant, an inert diluent and/or a disintegrating agent.
In a preferred embodiment, phytochemical is mixed with a binder, such as microcrystalline cellulose, and a surfactant, such as sodium lauryl sulphate until a homogeneous mixture is obtained. Subsequently, another binder, such as polyvidone, is transferred to the mixture under stirring with a small amount of added water. This mixture is passed through granulating sieves and dried by desiccation before compression into tablets in a standard tableting apparatus.
A tablet may be coated or uncoated. An uncoated tablet may be scored. A coated tablet may be coated with sugar, shellac, film or other enteric coating agents.
Therapeutic formulations suitable for parenteral administration include sterile solutions or suspensions of the active constituents. An aqueous or oily carrier may be used. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Formulations for parenteral administration also include a lyophilized powder comprising phytochemical that is to be reconstituted by dissolving in a pharmaceutically acceptable carrier that dissolves said phytochemical.
When the pharmaceutical composition is a capsule, it may contain a liquid carrier, such as a fatty oil, e.g., cacao butter.
Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
In yet another embodiment, the therapeutic compound can be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); see also Levy et al., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); Howard et al., J. Neurosurg. 71:105 (1989)).
Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990)).
In one embodiment of the pharmaceutical composition according to the invention, two or more active constituents are comprised as separate entities. The two entities may be administered simultaneously or sequentially.
The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
The invention is further explained by the following illustrative examples.